The present invention relates to the treatment of biological fluids with sterilizing radiation to inactivate various pathogens, such as viruses, in human plasma. In particular, the present invention relates to a device and method for inactivating pathogens in therapeutic fluids with sterilizing radiation in a continuous flow arrangement while exhibiting radiation dose uniformity.
In the transfusion and infusion medicine field, beneficial fluids are introduced to a patient for therapeutic purposes. Many of these fluids are of biologic origin, such as blood, plasma, or various fractions of blood or plasma. For example, blood plasma protein Factor VIII, which promotes blood coagulation to prevent life threatening bleeding, is used for maintaining hemostasis for hemophilic patients who lack the Factor VIII. Another example is plasma-derived immunoglobulin, which is used for strengthening and supplementing a patient""s immune defense. Contamination of such fluids with donor blood borne pathogens, such as viruses and other microorganisms, can be detrimental to the patient""s health and may even result in death of the patient. Therefore, methods must be set in place to substantially eliminate these pathogens before these fluids are introduced to the patient while minimizing the denaturation of useful fluid components during the pathogen inactivation process.
Existing methods for pathogen inactivation include detergent treatment for inactivating lipid-enveloped viruses, thermal treatment, and chemical and photochemical treatment for rendering various viral agents innocuous. Some of the photochemical treatment methods are described in U.S. Pat. Nos. 5,683,661, 5,854,967, 5,972,593, and the references cited therein. However, these methods tend to be less conducive to high volume and continuous processing applications, such as a production line for the manufacture of Factor VIII or immunoglobulin. These methods are also expensive.
Sterilizing radiation in the form of short ultraviolet (UV) wavelengths, gamma radiation or electron beam (beta) radiation has been found to be effective for inactivation of a broad range of pathogens. The use of a sterilizing radiation process is typically more economical than chemical treatments. Sterilizing radiation is defined as electromagnetic radiation capable of rupturing bonds in the genetic nucleaic acids (DNA) of pathogens. Nucleaic acids are typically much more susceptible to damage by sterilizing radiation than the protein products treated.
U.S. Pat. Nos. 5,133,932 describes an apparatus for batch treatment of biological fluids with ultraviolet radiation. However, the batch processing method disclosed causes irradiation of the fluids in a spatially uneven manner. Furthermore, the random and chaotic agitation process disclosed causes broad exposure time for various fluid components. This uneven exposure may cause inconsistent radiation dosage, which may result in ineffective pathogen removal (underexposure) or damage to beneficial biological agents (overexposure).
A continuous flow process for the irradiation of biological fluids is more effective than batch processing and is more conducive to high volume production. In a continuous flow process involving a constant sterilizing radiation illumination field, the transit time, or residence time, of the fluid is directly related to the radiation dose received by the fluid. Therefore, a continuous flow treatment process requires that the distribution of the residence times of the fluid elements be as narrow as possible. By analogy with the batch process, short residence time distributions lead to an insufficient inactivation dose of radiation and long residence time distributions could lead to damage and reduced potency of beneficial biological agents.
Present continuous flow methods involve fluid flow in a channel. A parabolic velocity profile exists for such fluid flow. In this profile, the fluid at the center of the channel is traveling at maximum velocity and the fluid close to the channel wall remains nearly stationary. Therefore, the residence time is the shortest for the maximum velocity at the center and increases for successive portions of the flow profile moving radially outwardly from the center. In the absence of turbulence or mechanical agitation, the flow volume near the channel walls would have an extremely long residence time. Thus, the flow volume near the channel walls runs the risk of overexposure to the radiation. In addition, if the particular channel wall is on the proximal side of the radiation source, very serious overexposure of the biological fluid can occur.
In addition to residence time distribution, the penetration depth of sterilizing radiation into various biological fluids is also a factor in controlling consistent radiation dosage of the fluid. Depending on the optical density of a particular biological fluid, the penetration of sterilizing radiation into the fluid can be very shallow. This is especially true in the case of low or moderate energy accelerated electrons or short wavelength UV radiation. For example, the penetration of 200 Kev electrons into water is less than 0.5 microns (20 mils). Similarly, UV radiation at 250 nm wavelength loses half of the intensity in human plasma at about a 75 micron (about 3 mils) penetration. Thus, a relatively thin fluid flow path can be advantageous in providing a more uniform
International Application No. PCT/GB97/01454 describes a UV irradiation apparatus that utilizes a static mixer disposed within a cylindrical fluid passage to facilitate mixing of the fluid. The apparatus also incorporates a heat exchanger to control the fluid temperature and prevent localized heating during irradiation. The localized heating purportedly causes the formation of insoluble particles of material. These particles may screen pathogens from the UV radiation, and, therefore, the ""01454 patent application provides a heat exchanger to reduce the likelihood that these particles will form. However, this apparatus focuses on the control of fluid temperature rather than control of residence time distributions of the fluid. The presence of the static mixer increases the flow resistance and has a significant adverse effect on the residence time distribution of the fluid and also significantly increases the pressure head 6f the fluid flow, thereby making this device less conducive to high volume throughput. Furthermore, the deep channels formed between the screw elements is conducive to non-uniform radiation dosage of the fluid despite the mixing of the fluid. This apparatus does not provide a controlled method for dealing with non-uniform dose exposure due to shallow penetration depth.
It is therefore an object of the present invention to provide a continuous flow device and method that is highly effective in uniformly irradiating high optical density fluids having low radiation penetrations.
It is also an object of the present invention to provide a continuous flow device and method for pathogen inactivation of biological fluids with sterilizing radiation utilizing a controlled and predictable mixing of the fluid that promotes a more uniform radiation exposure for fluids having high optical densities.
It is also an object of the present invention to provide a continuous flow device and method that provides radial mixing of the fluid with minimal pressure drop in the fluid flow.
It is also an object of the present invention to provide a continuous flow device and method that provides a uniform and narrow residence time distribution of the fluid within the device, thereby providing yet another control over radiation exposure.
It is another object of the present invention to provide a continuous flow device and method having a minimal air/fluid interface, thereby minimizing protein degradation in the fluid.
It is another object of the present invention to a continuous flow device and method that minimizes shear stress and shear induced degradation of high protein fluid products.
It is another object of the present invention to provide a continuous flow device and method that is scalable and therefore capable of high volume throughput that is conducive to manufacturing production lines.
It is another object of the present invention to provide a continuous flow device and method that is economical and cost effective.
It is another object of the present invention to provide a continuous flow device and method that is adaptable to various different radiation sources.
It is another object of the present invention to provide a continuous flow device and method that allows for ease of cleaning.
It is another object of the present invention to provide a continuous flow device and method that is capable of validation, i.e., demonstration of efficacy, reproducibility and reliability through scientific principles.
These and other objects will be readily apparent after reviewing the description and drawings herein.
The present invention is a device and method for inactivating pathogens in biological fluids with sterilizing radiation in a continuous flow path arrangement that exhibits radiation dose uniformity and narrow residence time distribution of the fluid within the device. The device also provides controlled and predictable rotation of the fluid through the generation of a secondary flow, which contributes to the control of radiation exposure of the fluid. The device is particularly effective in providing radiation dose uniformity for fluids having high optical densities.
The device comprises a radiation permeable cylindrical tube having a concentric cylindrical rotor disposed within the tube, thereby providing a relatively thin gap therebetween. A top and bottom plate seal the tube. The top and bottom plates are held together with tie rods. The bottom plate has a fluid inlet in fluid communication with the thin gap between the tube and the rotor. The top plate has a fluid outlet that is likewise in fluid communication with the gap between the tube and the rotor. The bottom plate is secured to a base, which contains a drive controller and a motor having a drive shaft. A rotor shaft is disposed axially through the cylindrical rotor and extends through a rotor aperture in the bottom plate. The rotor shaft also extends through an aperture in the base and is mechanically connected to the motor via a rotor shaft gear and a motor gear on the drive shaft of the motor.
A pump or other means provides fluid flow through the device from the inlet in the bottom plate to the outlet in the top plate. As the fluid flows upwardly through the device, a radiation source provides sterilizing irradiation of the fluid through the tube. The radiation source provides sterilizing UV radiation at the optimal wavelengths for the particular fluid. The gap between the tube and the rotor is designed to provide a high flow rate of the fluid with minimal pressure drop in the fluid flow. As the fluid flows, the motor drives the rotor to impart a secondary flow within the fluid in the form of Taylor vortices, which exchanges the fluid closer to the tube with the fluid closer to the rotor. The controlled and predictable mixing caused by the Taylor vortices provides a uniform radiation dosage of the fluid flowing through the device. The device also exhibits a narrow residence time distribution of the fluid within the device.
In another embodiment, the device comprises a relatively flat rigid fluid chamber having a radiation permeable flat top surface, an inner bottom surface and a fluid inlet and a fluid outlet. The chamber has angled side surfaces projecting outwardly from the fluid inlet and forming a diffuser for a fluid flowing through the inlet. The outlet of the chamber may also be configured with angled side surfaces to reduce the pressure head at the outlet. A radiation source is provided adjacent to the top surface of the chamber. A cascading base having a cascading upper surface is disposed on the inner bottom surface within the fluid chamber. The cascading upper surface has a plurality of humps that create a cascading effect on a fluid as it flows through the chamber. As the fluid flows through the chamber, a thin film of fluid falls over each hump and is exposed to the radiation passing through the high transparency plate. The cascading base geometry imparts a secondary flow within the fluid in the form of an eddy formation. The eddy formation provides controlled and predictable mixing of the fluid to insure uniform radiation exposure of the fluid.